Tumor-specific transcriptional targeting of suicide gene therapy

Qiao, Jian; Doubrovin, Mikhail; Sauter, Bv V.; Huang, Yong; Zs, Guo; Balatoni, Julius; Akhurst, Timothy; Blasberg, Ron G.; Tjuvajev, Jg G.; Chen, S.-H.; Woo, S. L. C.

doi:10.1038/sj.gt.3301618

Cited by 114 publications

(81 citation statements)

References 24 publications

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“…1 Intracellular targeting can also be facilitated by transcriptionally programming viruses to replicate within malignant tissue by substituting viral promoters with cellular promoter elements. [177][178][179][180][181][182][183] For example, poliovirus has been detargeted from nondividing neuronal cells and retargeted to replicate in malignant glioma cells by exchanging internal ribosomal entry site (IRES) elements from rhinovirus to polio. 184 The combination of a 3 0 polio UTR sequence with a 5 0 rhinovirus IRES element creates a chimeric virus that is incapable of efficient translation in neuronal cells, but is well translated in malignant cells.…”

Section: Oncolytic Viral Therapies E Lin and J Nemunaitismentioning

confidence: 99%

Oncolytic viral therapies

2004

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Molecular research has vastly advanced our understanding of the mechanism of cancer growth and spread. Targeted approaches utilizing molecular science have yielded provocative results in the treatment of cancer. Oncolytic viruses genetically programmed to replicate within cancer cells and directly induce toxic effect via cell lysis or apoptosis are currently being explored in the clinic. Safety has been confirmed and despite variable efficacy results several dramatic responses have been observed with some oncolytic viruses. This review summarizes results of clinical trials with oncolytic viruses in cancer.

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Section: Oncolytic Viral Therapies E Lin and J Nemunaitismentioning

confidence: 99%

Oncolytic viral therapies

2004

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“…The fidelity of this prostate-targeted TSTAfirefly luciferase (FL) expression cassette was maintained when inserted into an adenoviral vector, AdTSTA-FL [46]. Many applications of this two-tiered amplification strategy have been documented, including amplification of PSA promoter-mediated polyglutamine expression to treat prostate cancer [47], enhancement of the CEA promoter [48] and Muc-1-mediated expression for colon cancer [49].…”

Section: Augmenting Cancer-specific Expressionmentioning

confidence: 99%

Transcriptionally targeted gene therapy to detect and treat cancer

Wu¹,

Johnson²,

Sato³

2003

Trends in Molecular Medicine

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The greatest challenge in cancer treatment is to achieve the highest levels of specificity and efficacy. Cancer gene therapy could be designed specifically to express therapeutic genes to induce cancer cell destruction. Cancer-specific promoters are useful tools to accomplish targeted expression; however, high levels of gene expression are needed to achieve therapeutic efficacy. Incorporating an imaging reporter gene in tandem with the therapeutic gene will allow tangible proof of principle that gene expression occurs at the correct location and at a sufficient level. Gene-based imaging can advance cancer detection and diagnosis. By combining the cancer-targeted imaging and therapeutic strategies, the exciting prospect of a 'one-two punch' to find hidden, disseminated cancer cells and destroy them simultaneously can potentially be realized.Multiple genetic alterations that confer growth advantages to tumor cells are accumulated during the transformation from normal to neoplastic growth [1]. The loss of growth suppressive genes or gain of oncogenes constitutes a common mechanism of oncogenesis. Based on this information, a rational therapeutic approach is to re-introduce the defective growth control genes into tumor cells. In addition, approaches of inducing apoptotic responses and enhancing anti-tumor immune responses have also been employed [2]. Due to the availability of multiple flexible therapeutic strategies, gene therapy is being actively investigated in clinical settings.Among the ~ 40 ongoing gene therapy clinical trials for cancer (searched via www.clinicaltrials.gov/), 18 of the trial protocols involve an immune activating scheme, ten studies employ a genetic correction strategy and five use a cytotoxic gene. With regard to genetic correction strategies, p53 is a major target. The recombinant adenovirus is the dominant viral gene delivery vector, and it is employed in 18 protocols. However, none of 40 protocols use a cancer-specific gene expression strategy. An oncolytic adenovirus CN706 containing prostate-specific antigen (PSA) promoter driven viral replication [3] is being evaluated in phase II clinical trial for prostate cancer [4].Because the goal of cancer gene therapy is to eradicate cancer cells, many therapeutic genes could be detrimental if unintentionally expressed in normal cells. Selectively targeting the cancer cells is useful to achieve safety and efficacy, especially when the gene therapy vector is directly delivered into patients. Based on features that distinguish cancerous from normal cells, three targeting strategies could be employed. Transcriptional targeting takes advantage of the fact that some cancer cells express a subset of exclusive genes, and uses these cancerspecific promoters to express the desired transgenes [5]. Transductional targeting refers to surface modification on the gene delivery vehicle to enhance interactions with the cancer cell membrane antigen, thereby improving gene transfer into the cancerous cell. A third promising approach is to exploit cancer-a...

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“…Consequently, most TSPs that have been investigated for the purposes of reducing expression in nontarget organs unfortunately also demonstrate lower activity in target tissues. 17,18 Therefore, an important finding in this study was that it was possible to reconstitute gene delivery ( Figure 1) and cell killing (Figure 3) to the level obtained with the CMV promoter, while further decreasing transgene expression in normal tissues. Remarkably, the same was true in primary ovarian cancer cells purified from patient ascites ( Figure 2) and in an orthotopic model of disseminated ovarian cancer (Figure 4).…”

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confidence: 73%

Combined transcriptional and transductional targeting improves the specificity and efficacy of adenoviral gene delivery to ovarian carcinoma

et al. 2003

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Adenoviruses are efficient gene delivery vehicles but have broad native tropism. To this end, finding ways to target this virus specifically to carcinomas has become an important focus of cancer gene therapy. Transductional and transcriptional forms of targeting have been used with promising results in ovarian carcinoma. Therefore, we combined both forms of targeting to investigate the effect on the specificity and efficiency of transgene expression in this disease. We used the tissue-specific SLPI promoter and the ovarian cancer associated targeting adaptor protein, sCARfC6.5. This bispecific protein contains the coxsackie-adenovirus receptor ectodomain and a single-chain antibody specific for c-erbB-2. Viruses containing the SLPI or the ubiquitously expressed CMV promoter, with or without sCARfC6.5, were used for infection of ovarian cancer cell lines, primary ovarian tumor cells, and in an orthotopic model of disseminated ovarian carcinoma. This dual-targeting strategy increased the efficiency and specificity of transgene expression in vitro in reporter and cell-killing assays, and in vivo. By using both the SLPI promoter and sCARfC6.5, transgene expression was increased in ovarian tumors and decreased in normal tissues, including the liver. Thus, we show that combining transcriptional and transductional targeting can increase the efficacy and specificity of adenoviral gene therapy for ovarian carcinoma.

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Tumor-specific transcriptional targeting of suicide gene therapy

Cited by 114 publications

References 24 publications

Oncolytic viral therapies

Oncolytic viral therapies

Transcriptionally targeted gene therapy to detect and treat cancer

Combined transcriptional and transductional targeting improves the specificity and efficacy of adenoviral gene delivery to ovarian carcinoma

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